Studying viruses with respiratory organoids
It sounds like science fiction: growing respiratory organoids from the stem cells of cattle, pigs or humans. Researchers from Wageningen University & Research are working on these organoids and will soon expose them to viruses or bacteria to see whether they cause infections and can be transmitted to other animal species or humans. This stem cell technology will enable researchers to understand new pathogens more quickly and thus help to prevent major disease outbreaks such as COVID-19. And another important advantage: fewer animal experiments are required.
Farms or markets with livestock or wild animals such as chickens, bats or minks can be hotspots for zoonoses (pathogens that can be transmitted from animals to humans). This transmission usually occurs through the air, but people and animals can sometimes become infected through food or water.
“Animals harbour various respiratory viruses that are sometimes pathogenic for humans,” says virologist Rik de Swart. “One example is SARS, a coronavirus that originates from bats and sometimes causes a fatal lung infection in humans. If someone comes into contact with such a virus, the immune system tries to destroy it. As soon as a cell detects the intruder, it sounds the alarm by producing proteins called interferons. This warns the surrounding cells in the tissue, which then strengthen their antiviral defences. But some virus infections manage to circumvent this response, for example by blocking the interferon production of cells. To prevent major disease outbreaks, it is important to identify and understand new pathogens as soon as possible.”
Organoids from stem cells simulate respiratory tract
To test viruses, the researchers are therefore growing organoids (mini-organs) that simulate the respiratory tract. They start with stem cells from cattle, pigs, goats, cats, dogs, rabbits, ferrets and humans. To acquire the stem cells they take a tissue sample (biopsy) from the respiratory tract and cut it into small pieces to remove individual cells. They then place the cells in a gel that is enriched with extracellular matrix proteins and they add growth factors. As a result the stem cells grow into small clumps of cells that are barely visible to the naked eye.
De Swart: “These organoids consist of various types of cells, so they are a good model of the organ from which they are derived. We use these organoids to create a cell bank that is stored in a freezer. We can then conduct studies with these tiny cell systems, such as virus infection studies; this approach can replace the animal experiments that are currently needed for such studies.”
According to De Swart, the organoids enable researchers to predict the effects of a virus and which animal species it can infect. As a test case, they are infecting these respiratory organoids with avian influenza virus. “We know that this virus can be transmitted from birds to pigs and humans. We are studying whether this virus grows well on pig and human cell culture models and not on models from other species: does the virus cause an infection and is it able to spread within the cell culture? We hope and expect that the rate of spread in organoids is a good predictor of the rate of spread in the various hosts.”
We are particularly interested in studying viruses that bypass the initial immune response. These results are important for health authorities, who can make better decisions about which specific viruses need to be monitored more closely to prevent a major virus outbreak or pandemic.
At least three families of respiratory viruses have the ability to jump from animals to humans A century ago, for example, a global pandemic was caused by an influenza virus, the Spanish Flu. In addition, there are coronaviruses such as SARS. De Swart: “We estimate that in addition to the flu viruses and coronaviruses, the paramyxoviruses, especially Nipah and Hendra virus, are potential candidates for future zoonotic diseases and possibly even a subsequent pandemic. These paramyxoviruses jump from bats via horses or pigs to humans. With the help of the respiratoryorganoids from various animal species, we hope that we can soon determine the extent to which these and other viruses pose a risk to humans.”